Ectopic Adrenocorticotropic Hormone Production in a Stage IV Neuroendocrine Tumor: A Rare Presentation of Cushing’s Syndrome

Posted on April 25, 2025 by MaryO

Abstract

Neuroendocrine tumors (NETs) are heterogeneous neoplasms that arise from neuroendocrine cells, resulting in endocrine imbalances that impact quality of life and prognosis. Ectopic adrenocorticotropic hormone (ACTH) production by NETs is a rare cause of ACTH-dependent Cushing’s syndrome. While the majority of these cases are associated with intrathoracic tumors, recent reports have indicated an increasing incidence of cases originating from diverse anatomical sites. Furthermore, despite comprehensive imaging efforts, a substantial proportion of cases remain challenging to localize.

In this case, we describe a 54-year-old man with a stage IV NET with metastatic liver and pancreatic lesions, who presented with Cushing’s syndrome due to ectopic ACTH production. The patient exhibited symptoms of severe hypercortisolism, including weight gain, proximal muscle weakness, acute-onset heart failure, and hypertension. Imaging revealed bilateral adrenal hypertrophy. Laboratory tests revealed hypokalemia and hyperglycemia and confirmed elevated cortisol levels and a lack of suppression after dexamethasone administration, consistent with ectopic rather than pituitary ACTH production. The patient was treated with metyrapone because ketoconazole was contraindicated because of liver metastasis and recent upper gastrointestinal bleeding requiring proton pump inhibitor use. This case highlights the rare occurrence of ACTH-producing NETs and emphasizes the importance of considering this diagnosis in cases with similar presentations. Furthermore, medical management of this patient without surgical intervention, owing to multiple contraindications, offers an important perspective for treating complex cases.

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that can secrete various hormones; however, ectopic adrenocorticotropic hormone (ACTH) production is rare, occurring in only 5-10% of all Cushing’s syndrome cases [1]. Liddle et al. described the first case in 1962 [2]. A recent case series that examined the clinical and diagnostic treatment of ectopic ACTH in a tertiary center included information on only 12 cases collected over a 17-year period [3]. The most common site for ectopic ACTH from malignancy is the intrathoracic region, primarily in small-cell lung carcinomas. Unfortunately, obtaining a single diagnostic image that can detect tumor-producing ACTH remains challenging. According to the literature, ectopic ACTH resulting in Cushing’s syndrome can remain undetected [3,4].

In the present case, a patient with a stage IV NET presented with the classic features of Cushing’s syndrome, leading to the diagnosis of ectopic ACTH production. The complexity of this case, owing to the patient’s metastatic disease, the contraindications for certain therapies, and the requirement for atypical medical management, highlights the challenges of treating advanced NETs, especially metastatic lesions with hormonal overproduction. This report aimed to underscore the importance of early recognition and the effectiveness of metyrapone as a treatment for hypercortisolism in metastatic NET.

Case Presentation

A 54-year-old man with a known history of a World Health Organization (WHO) grade 3, stage IV NET with metastatic lesions in the liver and pancreas presented to the hospital with new-onset acute heart failure. His medical history consisted of papillary thyroid cancer diagnosed in January 2023, for which he underwent total thyroidectomy and left neck dissection. Three months later, the patient was found to have a new liver lesion that was biopsied and was consistent with a WHO grade 3 NET (Figure 1). He was started on capecitabine and temozolomide chemotherapy regimen, which was switched to folinic acid, fluorouracil, and oxaliplatin due to disease progression. He had undergone positron emission tomography (PET)/computed tomography (CT) as part of the follow-up for NET, and the findings were consistent with hypermetabolic pancreatic and liver lesions. However, no uptake was observed in the lungs and/or adrenal glands (Figure 2).

Liver-tissue-section-showing-positive-synaptophysin-immunohistochemical-staining-in-neoplastic-cells,-consistent-with-a-neuroendocrine-neoplasm.
Figure 1: Liver tissue section showing positive synaptophysin immunohistochemical staining in neoplastic cells, consistent with a neuroendocrine neoplasm.
FDG-PET/CT-scan-of-the-whole-body-showing-hypermetabolic-pancreatic-tail-mass-which-measures-up-to-6.5-cm-and-multifocal-liver-hypermetabolic-metastases.-
Figure 2: FDG PET/CT scan of the whole body showing hypermetabolic pancreatic tail mass which measures up to 6.5 cm and multifocal liver hypermetabolic metastases.

FDG: fluorodeoxyglucose; PET: positron emission tomography; CT: computed tomography

The patient was admitted first with gastrointestinal (GI) bleeding secondary to duodenal ulcers that were managed with a proton pump inhibitor (PPI), pantoprazole 40 mg, oral, BID (Figure 3). Ten days later, he presented with worsening dyspnea and shortness of breath, and clinical examination was consistent with volume overload and 4+ pitting edema in the lower extremities. Additionally, he was found to have a significantly low potassium level (2.6 mmol/L) and worsening serum blood glucose (341 mg/dL). The constellation of symptoms in the patient, including significant weight gain, obesity, easy bruising, proximal muscle weakness, acute-onset heart failure, hypertension, hypokalemia, and worsening hyperglycemia with new insulin requirements, raised concerns about hypercortisolism and prompted testing. The serum ACTH levels were markedly elevated (488 pg/mL; reference range: 10-60 pg/mL). CT of the abdomen and pelvis revealed bilateral adrenal gland hypertrophy (Figure 4).

Upper-endoscopy-images-showing-four-cratered,-non-bleeding-duodenal-ulcers-with-a-clean-ulcer-base-(Forrest-Class-III).
Figure 3: Upper endoscopy images showing four cratered, non-bleeding duodenal ulcers with a clean ulcer base (Forrest Class III).
CT-of-the-abdomen-and-pelvis-demonstrating-bilateral-adrenal-gland-hypertrophy.
Figure 4: CT of the abdomen and pelvis demonstrating bilateral adrenal gland hypertrophy.

CT: computed tomography

Morning cortisol levels were significantly increased (42.2 µg/dL), and the 8-mg dexamethasone suppression test showed no suppression, with a post-dexamethasone cortisol level of 44.2 µg/dL. The 24-hour urinary-free cortisol level was elevated (2259 µg/24 hour; reference range: 3.5-45 µg/24 hour). At this time, the differential diagnoses included but were not limited to Cushing’s disease or ectopic ACTH production secondary to metastatic NET. However, given that the patient had bilateral adrenal gland hypertrophy that was noted on imaging and his cortisol did not suppress with a high-dose dexamethasone suppression test, these findings support ectopic ACTH secretion secondary to metastatic NET over Cushing’s disease from a pituitary source. 

After confirming the diagnosis, the patient was started on metyrapone 500 mg, administered two times per day; his serum cortisol began to decrease (from 42 to 38 µg/dL) and continued to decline until it reached the lowest level (8.9 µg/dL) with metyrapone 500 mg, administered four times per day. Unfortunately, because of cost-related issues, the patient was switched to octreotide; however, subsequently, his serum cortisol level increased (from 8.9 to 49 µg/dL). Ketoconazole was not a viable option because of drug-drug interactions with PPI. Alternative suppressive medications were considered and included osilodrostat and mifepristone. However, given the patient’s QTc prolongation and previous history of arrhythmia, it was felt that the use of these medications was too high risk for fatal arrhythmia. Given the limited medical options, the patient was evaluated for surgery, and, given the multiple comorbidities as well as metastatic disease without an apparent culprit lesion, he was not initially deemed to be a suitable surgical candidate. Therefore, metyrapone was reinitiated to control hypercortisolemia while the patient was admitted, and it effectively lowered his total serum cortisol levels. However, given that metyrapone was not a long-term option and medical management had failed (octreotide was ineffective in controlling serum cortisol levels, and ketoconazole could not be used due to drug-to-drug interactions with PPI), surgery was considered as an option. Despite the high risk associated with the procedures owing to the patient’s condition, bilateral adrenalectomy was performed, considering the lack of medical options and the patient’s goals of care. The patient was discharged home on oral hydrocortisone, 15 mg in the morning and 10 mg in the evening, in addition to fludrocortisone 0.1 mg daily. The patient’s body surface area is 2.5 m². The pathology of his adrenal glands was consistent with that of a metastatic NET (Figure 5). The patient was seen in the endocrinology clinic after bilateral adrenalectomy for a follow-up almost one month after the procedure. He reported feeling tired and falling asleep quite often. He used to be able to walk; however, now, he could only make it a quarter of the way due to muscle weakness. Unfortunately, further follow-up and outcome could not be evaluated as the patient died three months after his bilateral adrenalectomy surgery, and the cause of death was unknown.

Adrenal-tissue-section-showing-positive-synaptophysin-immunohistochemical-staining-in-neoplastic-cells,-consistent-with-a-neuroendocrine-neoplasm.
Figure 5: Adrenal tissue section showing positive synaptophysin immunohistochemical staining in neoplastic cells, consistent with a neuroendocrine neoplasm.

Discussion

This case of a stage IV NET with ectopic ACTH production leading to Cushing’s syndrome is notable because of its rarity and complexity. Although NETs are known for their diverse hormonal secretions, only a small subset of them are associated with ACTH production, making this case an important addition to the limited literature.

NETs causing ectopic Cushing’s syndrome are most frequently found in the intrathoracic region (40-60%), including bronchial tumors, small-cell lung carcinoma, and thymic carcinomas. Additional sites where these tumors may occur include the pancreas and thyroid gland (particularly medullary thyroid carcinoma). Less common locations include the prostate, rectum, ovaries, and bladder [5].

Our patient’s PET/CT findings were consistent with those of hypermetabolic lesions in the liver and pancreas. However, there was no uptake in the lungs, which is the most common site reported in the literature [5]. Additionally, there was no uptake in the adrenal glands, and the pathology was later found to be consistent with NETs. This posed a challenge to the diagnosis and identification of the culprit lesion. Reportedly, high-resolution cross-sectional CT imaging has a sensitivity of 50-67% in identifying the source of ectopic ACTH production, and when the findings are negative, a variety of nuclear medicine functional imaging techniques (Octreoscan, fluorine-18 fluorodeoxyglucose PET/CT, and gallium-68 somatostatin receptor-targeted PET/CT) can be used [6]. However, despite advances in imaging modalities, up to 20% of ectopic ACTH syndrome cases remain occult after initial imaging [4,7]. 

ACTH-producing pancreatic neuroendocrine (pNE) tumors are rare malignancies characterized by their aggressive nature [8]. Individuals diagnosed with this condition have less favorable outcomes compared with those with insulinoma, gastrinoma, or nonfunctional ACTH-producing pNE tumors [9]. The underlying reasons for the aggressiveness of the tumor and the resulting poor patient outcomes remain elusive. One study proposed that decreased methylation of the proopiomelanocortin promoter may enhance the ability of the tumors to secrete ACTH [10].

A similar presentation was reported by Al-Toubah et al. in a 2023 case series on ACTH-secreting pNE neoplasms. That study highlighted the rarity of ACTH production in these tumors and emphasized that such cases often present with severe hypercortisolemia and Cushing’s syndrome. However, most patients in their series were treated with ketoconazole, which was not an option for our patient because of liver metastasis and recent upper GI bleeding requiring PPI treatment [11].

A systematic review published in February 2021 by Wu et al. investigated ACTH-producing pNE tumors. That study analyzed 210 publications, including data from 336 patients diagnosed with this condition. The results indicated a higher prevalence among female individuals (66.4%), at an average age of 44.7 years. The review reported the following frequencies of clinical symptoms: 69.3% experienced hypokalemia, 63.2% developed diabetes, 60.1% suffered from weakness, 56.4% had hypertension, 41.1% displayed moon face, and 37.4% presented with edema [12].

In the present case, the patient presented with decompensated heart failure, which is consistent with various case reports describing acute decompensated heart failure as the first presentation. Sugihara et al. reported three cases of Cushing’s syndrome characterized by left ventricular failure as the predominant feature associated with gross left ventricular hypertrophy [13]. Similarly, Petramala et al. reported a case of a 28-year-old woman with Cushing’s syndrome secondary to an adrenal adenoma who exhibited congestive heart failure as an initial symptom [14]. In this regard, some studies have examined the relationship between cardiac dysfunction and hypercortisolism and found that cardiac remodeling is independent of hypertension and is probably related to the direct action of cortisol on myocardial tissue via glucocorticoid receptors [15,16]. These cardiac impairments may be reversible with the appropriate treatment of the underlying hypercortisolism, such as the surgical resection of the adrenal adenoma or pituitary adenoma, and the medical management of heart failure [14].

Our patient received metyrapone and could not be treated using ketoconazole because of liver metastasis and drug-drug interactions with PPI, as previously mentioned. In 2022, Landry et al. studied the management of ACTH-secreting NETs [17]. Their study, including 76 patients, found that most patients had metastatic disease at the time of ectopic Cushing’s syndrome diagnosis, similar to our case. Furthermore, they found that de novo hyperglycemia predicted worse survival outcomes. Therefore, controlling the hypercortisolic phase is crucial. Unfortunately, most patients present with metastatic disease, which makes surgical management, that is, removing the ACTH-producing tumor, not always an option. Additionally, they found that patients with medically resistant ectopic Cushing’s syndrome, subsequently controlled with bilateral adrenalectomy, had significantly better disease-specific survival following ectopic Cushing’s syndrome diagnosis than did patients who did not undergo bilateral adrenalectomy.

In our case, there were limited treatment options given the metastatic burden and limitations in using some of the medications to control hypercortisolism. In their article, Landry et al. stated “We have learned this over time as, unfortunately, most patients in our cohort who were diagnosed with resistant ectopic Cushing syndrome only used one type of suppression therapy by the end of the study” [17]. One medication, peptide receptor radionuclide therapy, was reported in multiple studies [5,18,19]. However, the Food and Drug Administration did not approve this therapy until 2018, and it has not been examined for ectopic Cushing’s disease, especially in the metastatic NET setting.

As surgical resection remains the recommended first-line treatment for the majority of patients with Cushing’s syndrome [20], medical therapy plays a critical role when surgery is not feasible; many studies reviewed the use of agents such as mifepristone [21], levoketoconazole [22], and pasireotide [23,24]. Additionally, a recent review study that focused on the clinical consideration for osilodrostat in the management of patients with ectopic ACTH found that quality of life improved during the use of long-term osilodrostat as a treatment for ectopic Cushing’s syndrome raised from a pNE tumor [25].

Conclusions

This case highlights the complexities involved in the diagnosis and management of ectopic ACTH-producing NETs. Due to the rarity of such presentations, clinicians must maintain a high index of suspicion for ectopic ACTH production in patients with unexplained hypercortisolism, particularly when signs of Cushing’s syndrome are present. Additionally, the management of preoperative hypercortisolism may be challenging, as in our patient. The treatment approach in this case was unconventional, given the patient’s ineligibility for surgery due to difficulties in localizing the exact lesion and the metastatic disease. Medical management with metyrapone was chosen. However, as it was cost-prohibitive, alternative therapy with octreotide was attempted, but it failed to achieve adequate control. Ketoconazole was not an option given the recent GI bleeding, and eventually, our patient underwent bilateral adrenalectomy. Therefore, future studies are required to develop predictive markers to determine which patients will benefit from bilateral adrenalectomy versus long-term pharmacotherapy. An extensive study on perioperative management in cases with ectopic ACTH would have proven to be useful in ensuring the survival of our patient.

References

  1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK: Cushing’s syndrome. Lancet. 2015, 386:913-27. 10.1016/S0140-6736(14)61375-1
  2. Liddle GW, Island DP, Ney RL, Nicholson WE, Shimizu N: Nonpituitary neoplasms and Cushing’s syndrome. Ectopic “adrenocorticotropin” produced by nonpituitary neoplasms as a cause of Cushing’s syndrome. Arch Intern Med. 1963, 111:471-5. 10.1001/archinte.1963.03620280071011
  3. González Fernández L, Maricel Rivas Montenegro A, Brox Torrecilla N, et al.: Ectopic Cushing’s syndrome: clinical, diagnostic, treatment and follow-up outcomes of 12 cases of lung ectopic ACTH. Endocrinol Diabetes Metab Case Rep. 2023, 2023:22-0378. 10.1530/EDM-22-0378
  4. Varlamov E, Hinojosa-Amaya JM, Stack M, Fleseriu M: Diagnostic utility of gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience. Pituitary. 2019, 22:445-55. 10.1007/s11102-019-00972-w
  5. Davi’ MV, Cosaro E, Piacentini S, et al.: Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017, 176:453-61. 10.1530/EJE-16-0809
  6. Frete C, Corcuff JB, Kuhn E, et al.: Non-invasive diagnostic strategy in ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2020, 105:3273-84. 10.1210/clinem/dgaa409
  7. Zisser L, Kulterer OC, Itariu B, et al.: Diagnostic role of PET/CT tracers in the detection and localization of tumours responsible for ectopic Cushing’s syndrome. Anticancer Res. 2021, 41:2477-84. 10.21873/anticanres.15024
  8. Falconi M, Eriksson B, Kaltsas G, et al.: ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016, 103:153-71. 10.1159/000443171
  9. Maragliano R, Vanoli A, Albarello L, et al.: ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J Surg Pathol. 2015, 39:374-82. 10.1097/PAS.0000000000000340
  10. Zhang C, Jin J, Xie J, et al.: The clinical features and molecular mechanisms of ACTH-secreting pancreatic neuroendocrine tumors. J Clin Endocrinol Metab. 2020, 105:3449-58. 10.1210/clinem/dgaa507
  11. Al-Toubah T, Pelle E, Hallanger-Johnson J, Haider M, Strosberg J: ACTH-secreting pancreatic neuroendocrine neoplasms: a case-series. J Neuroendocrinol. 2023, 35:e13336. 10.1111/jne.13336
  12. Wu Y, Xiong G, Zhang H, Wang M, Zhu F, Qin R: Adrenocorticotropic hormone-producing pancreatic neuroendocrine neoplasms: a systematic review. Endocr Pract. 2021, 27:152-7. 10.1016/j.eprac.2020.10.012
  13. Sugihara N, Shimizu M, Shimizu K, Ino H, Miyamori I, Nakabayashi H, Takeda R: Disproportionate hypertrophy of the interventricular septum and its regression in Cushing’s syndrome. Report of three cases. Intern Med. 1992, 31:407-13. 10.2169/internalmedicine.31.407
  14. Petramala L, Battisti P, Lauri G, et al.: Cushing’s syndrome patient who exhibited congestive heart failure. J Endocrinol Invest. 2007, 30:525-8. 10.1007/BF03346339
  15. Fallo F, Budano S, Sonino N, Muiesan ML, Agabiti-Rosei E, Boscaro M: Left ventricular structural characteristics in Cushing’s syndrome. J Hum Hypertens. 1994, 8:509-13.
  16. Yiu KH, Marsan NA, Delgado V, et al.: Increased myocardial fibrosis and left ventricular dysfunction in Cushing’s syndrome. Eur J Endocrinol. 2012, 166:27-34. 10.1530/EJE-11-0601
  17. Landry JP, Clemente-Gutierrez U, Pieterman CR, et al.: Management of adrenocorticotropic hormone-secreting neuroendocrine tumors and the role of bilateral adrenalectomy in ectopic Cushing syndrome. Surgery. 2022, 172:559-66. 10.1016/j.surg.2022.03.014
  18. Cheung NW, Boyages SC: Failure of somatostatin analogue to control Cushing’s syndrome in two cases of ACTH-producing carcinoid tumours. Clin Endocrinol (Oxf). 1992, 36:361-7. 10.1111/j.1365-2265.1992.tb01461.x
  19. De Rosa G, Testa A, Liberale I, Pirronti T, Granone P, Picciocchi A: Successful treatment of ectopic Cushing’s syndrome with the long-acting somatostatin analog octreotide. Exp Clin Endocrinol. 1993, 101:319-25. 10.1055/s-0029-1211252
  20. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M: Cushing’s syndrome. Lancet. 2023, 402:2237-52. 10.1016/S0140-6736(23)01961-X
  21. Fleseriu M, Molitch ME, Gross C, Schteingart DE, Vaughan TB 3rd, Biller BM: A new therapeutic approach in the medical treatment of Cushing’s syndrome: glucocorticoid receptor blockade with mifepristone. Endocr Pract. 2013, 19:313-26. 10.4158/EP12149.RA
  22. Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BM: Levoketoconazole: a novel treatment for endogenous Cushing’s syndrome. Expert Rev Endocrinol Metab. 2021, 16:159-74. 10.1080/17446651.2021.1945440
  23. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF: Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary. 2014, 17:180-6. 10.1007/s11102-013-0483-3
  24. Trementino L, Cardinaletti M, Concettoni C, Marcelli G, Boscaro M, Arnaldi G: Up-to 5-year efficacy of pasireotide in a patient with Cushing’s disease and pre-existing diabetes: literature review and clinical practice considerations. Pituitary. 2015, 18:359-65. 10.1007/s11102-014-0582-9
  25. Fleseriu M, Auchus RJ, Bancos I, Biller BM: Osilodrostat treatment for adrenal and ectopic Cushing syndrome: integration of clinical studies with case presentations. J Endocr Soc. 2025, 9:bvaf027. 10.1210/jendso/bvaf027

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Ectopic Adrenocorticotrophic Hormone Syndrome in a 10-Year-Old Girl With a Thymic Neuroendocrine Tumor

Posted on November 29, 2024 by MaryO

Abstract

Background

Thymic neuroendocrine tumor as a cause of Cushing syndrome is extremely rare in children.

Case presentation

We report a case of a 10-year-old girl who presented with typical symptoms and signs of hypercortisolemia, including bone fractures, growth retardation, and kidney stones. The patient was managed with oral ketoconazole, during which she experienced adrenal insufficiency, possibly due to either cyclic adrenocorticotropic hormone (ACTH) secretion or concurrent COVID-19 infection. The patient underwent a diagnostic work-up which indicated the possibility of an ACTH-secreting pituitary neuroendocrine tumor. However, after a transsphenoidal surgery, the diagnosis was not confirmed on histopathological examination. Subsequent bilateral inferior petrosal sinus sampling showed strong indications of the presence of ectopic ACTH syndrome. Detailed rereading of functional imaging studies, including 18F-FDG PET/MRI and 68Ga DOTATOC PET/CT, ultimately identified a small lesion in the thymus. The patient underwent videothoracoscopic thymectomy that confirmed a neuroendocrine tumor with ACTH positivity on histopathological examination.

Conclusion

This case presents some unique challenges related to the diagnosis, management, and treatment of thymic neuroendocrine tumor in a child. We can conclude that ketoconazole treatment was effective in managing hypercortisolemia in our patient. Further, a combination of functional imaging studies can be a useful tool in locating the source of ectopic ACTH secretion. Lastly, in cases of discrepancy in the results of stimulation tests, bilateral inferior petrosal sinus sampling is highly recommended to differentiate between Cushing disease and ectopic ACTH syndrome.

Peer Review reports

Background

In children above seven years of age, the majority of pediatric Cushing syndrome (CS) cases are caused by a pituitary neuroendocrine tumors (PitNET). However, a differential diagnosis of hypercortisolemia in children is often challenging concerning the interpretation of stimulation tests and the fact that up to 50% of PitNET may not be detected on magnetic resonance imaging (MRI) [1]. An ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is extremely rare in children. Its diagnosis is often missed or confused with Cushing disease (CD) [2]. Most ACTH-secreting tumors originate from bronchial or thymic neuroendocrine tumors (NETs), or less commonly, from NETs in other locations. To diagnose EAS, specific functional imaging studies are often indicated to elucidate the source of ACTH production.

Pharmacotherapy may be used before surgery to control hypercortisolemia and its symptoms/signs, or in patients in whom the source of hypercortisolism has not been found (e.g., EAS), or surgery failed. Ketoconazole or metyrapone, as adrenal steroidogenesis blockers, were found to be very efficient, although they exhibit side effects [3].

Furthermore, cyclic secretion of ACTH followed by fluctuating plasma cortisol levels is extremely rare in children, including those with EAS [4, 5]. Therefore, in cyclic EAS, the use of steroid inhibitors or acute illness or trauma can be associated with adrenal insufficiency, which can be life-threatening. Here we describe the clinical features, laboratory and radiological investigations, results, management, and clinical outcome of a 10-year-old girl with a thymic NET presenting with ACTH secretion.

Case presentation

A 10-year-old girl was acutely admitted to our university hospital for evaluation of facial edema and macroscopic hematuria in May 2021. A day before admission, she presented to the emergency room for dysuria, pollakiuria, nausea, and pain in her right lower back. Over the past year she had experienced excessive weight gain with increased appetite and growth retardation (Fig. 1). Her height over three years had shifted from the 34th to the 13th centile (Fig. 1). Her parents noticed facial changes, pubic hair development, increased irritability, and moodiness.

Fig. 1

figure 1

Body weight, body height, and body mass index development of the case patient. The black arrow indicates the first presentation, the blue arrow indicates the start of ketoconazole treatment and the yellow arrow indicates the time of thymectomy. Mid-parental height is indicated by the green line

At admission, she was found to have a moon face with a plethora, few acne spots on forehead, as well as facial puffiness. In contrast to slim extremities, an abnormal fat accumulation was observed in the abdomen. Purple striae were present on abdomen and thighs. She did not present with any bruising, proximal myopathy, or edema. On physical examination, she was prepubertal, height was 135 cm (13th centile), and weight was 37 kg (69th centile) with a BMI of 20.4 kg/m2 (90th centile). She developed persistent hypertension. Her past medical history was uneventful except for two fractures of her upper left extremity after minimal trips one and three years ago, both treated with a caste. Apart from hypothyroidism on the maternal side, there was no history of endocrine abnormalities or tumors in the family.

In the emergency room, the patient was started on sulfonamide, pain medication, and intravenous (IV) fluids. Her hypertensive crises were treated orally with angiotensin-converting enzyme inhibitor or with a combination of adrenergic antagonists and serotonin agonists administered IV. Hypokalemia had initially been treated with IV infusion and then with oral potassium supplements. A low serum phosphate concentration required IV management. The initial investigation carried out in the emergency room found hematuria with trace proteinuria. Kidney ultrasound showed a 5 mm stone in her right ureter with a 20 mm hydronephrosis. She did not pass any kidney stones, however, fine white sand urine analysis reported 100% brushite stone.

Hypercortisolemia was confirmed by repeatedly increased 24-hour urinary free cortisol (UFC), (5011.9 nmol/day, normal range 79.0-590.0 nmol/day). Her midnight cortisol levels were elevated (961 nmol/l, normal range 68.2–537 nmol/l). There was no suppression of serum cortisol after 1 mg overnight dexamethasone suppression test (DST) or after low-dose DST (LDDST). An increased morning plasma ACTH (30.9 pmol/l, normal range 1.6–13.9 pmol/) suggested ACTH-dependent hypercortisolemia. There was no evidence of a PitNET on a 1T contrast-enhanced MRI. The high-dose DST (HDDST) did not induce cortisol suppression (cortisol 1112 nmol/l at 23:00, cortisol 1338 nmol/l at 8:00). Apart from the kidney stone, a contrast-enhanced computed tomography (CT) of her neck, chest, and abdomen/pelvis did not detect any lesion. Various tumor markers were negative and the concentration of chromogranin A was also normal.

A corticotropin-releasing hormone (CRH) stimulation test induced an increase in serum cortisol by 32% at 30 min and ACTH concentration by 67% at 15 min (Table 1). A 3T contrast-enhanced MRI scan of the brain identified a 3 × 2 mm lesion in the lateral right side of the pituitary gland (Fig. 2). An investigation of other pituitary hormones was unremarkable. Apart from low serum potassium (minimal level of 2.8 mmol/l; normal range 3.3–4.7 mmol/l) and phosphate (0.94 mmol/l; normal range 1.28–1.82 mmol/l) concentrations, electrolytes were normal. The bone mineral density assessed by whole dual-energy X-ray absorptiometry was normal.

Fig. 2

figure 2

Coronal and sagittal 3T contrast-enhanced brain MRI scans. A suspected 3 × 2 mm lesion in the lateral right side of the pituitary gland (yellow arrows)

The patient was presented at the multidisciplinary tumor board and it was decided that she undergoes transsphenoidal surgery for the pituitary lesion. No PitNET was detected on histopathological examination and no favorable biochemical changes were noted after surgery. After the patient recovered from surgery, subsequent bilateral inferior petrosal sinus sampling (BIPSS) confirmed EAS as the maximum ratio of central to peripheral ACTH concentrations was only 1.7. During the investigation for tumor localization, she was started on ketoconazole treatment (300 mg/day) to alleviate symptoms and signs of hypercortisolism. Treatment with ketoconazole had a beneficial effect on patient health (Fig. 1). There was a weight loss of 2 kg in a month, a disappearance of facial plethora, and a decrease in vigorous appetite. Her liver function tests remained within the normal range.

Table 1 Result of corticotropin-releasing hormone stimulation test

The 24-hour UFC excretion normalized three weeks after ketoconazole initiation. However, six weeks after continuing ketoconazole therapy (400 mg/day), the patient complained of nausea, vomiting, and diarrhea. She was found to have adrenal insufficiency with a low morning serum cortisol of 10.70 nmol/l (normal range 68.2–537 nmol/l) and salivary cortisol concentrations < 1.5 nmol/l (normal range 1.7–29 nmol/l). She was also found to be positive for COVID-19 infection. Ketoconazole treatment was stopped and our patient was educated to take stress steroids in case of persisting or worsening symptoms. Her clinical status gradually improved and steroids were not required.

Meanwhile, whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI was performed with no obvious hypermetabolic lesion suspicious of a tumor. No obvious accumulation was detected on 68Ga-DOTATOC PET/CT images (Fig. 3). However, a subsequent careful and detailed re-review of the images detected a discrete lesion on 18F-FDG PET/MRI and 68Ga-DOTATOC PET/CT scans in the left anterior mediastinum, in the thymus (Fig. 4).

Fig. 3

figure 3

18F-FDG PET/MRI (A) and 68Ga-DOTATOC (B) PET/CT scans. Whole body MIP reconstructions. Subtle correspondent focal hyperactivity in the left mediastinum (black arrow). The 18F-FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Fig. 4

figure 4

Axial slices of PET/MRI (A–C) and 68Ga-DOTATOC (D–F) PET/CT scans. Subtle correspondent focal hyperactivity in the left mediastinum (white arrow). No obvious finding on MRI (C) and CT (F) scans. The FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Three weeks after the episode of adrenal insufficiency and being off ketoconazole treatment, our patient´s pre-surgery laboratory tests showed slightly low morning cortisol 132 nmol/l with surprisingly normal ACTH 2.96 pmol/l (normal range 1.6–13.9 pmol/). Given the upcoming surgery, she was initiated on a maintenance dose of hydrocortisone (15 mg daily = 12.5 mg/m2/day). Further improvement of cushingoid characteristics (improvement of facial plethora and moon face, weight loss) was noticed. Our patient underwent videothoracoscopic surgery, and a hyperplastic thymus of 80 × 70 × 15 mm with a 4 mm nodule was successfully removed. Tumor immunohistochemistry was positive for ACTH, chromogranin A, CD56, and synaptophysin. Histopathological findings were consistent with a well-differentiated NET grade 1. A subsequent genetic screening did not detect any pathogenic variant in the MEN1 gene.

After surgery, hydrocortisone was switched to a stress dose and gradually decreased to a maintenance dose. Antihypertensive medication was stopped and further weight loss was observed after thymectomy. Within a few weeks after the thoracic surgery, the patient entered puberty, her mood improved significantly, and potassium supplements were stopped. Finally, hydrocortisone treatment was stopped ten months after thymectomy.

Discussion and conclusions

The case presented here demonstrates a particularly challenging work-up of the pediatric patient with the diagnosis of CS caused by EAS due to thymic NET. Differentiating CD and EAS can sometimes be difficult, including the use of various laboratory and stimulation tests and their interpretation, as well as proper, often challenging, reading of functional imaging modalities, especially if a discrete lesion is present at an unusual location [1]. When using established criteria for Cushing disease (for the CRH test an increase of cortisol and/or ACTH by ≥ 20% or ≥ 35%, respectively, and a ≥ 50% suppression of cortisol for the HDDST) our patient presented discordant results. The CRH stimulation test induced an increase in cortisol by 32% and ACTH by 67% and the 3T MRI pointed to the right-side pituitary lesion, both to yield false positive results. The HDDST, on the other hand, did not induce cortisol suppression and was against characteristic findings for CD. We did not proceed with desmopressin testing, which also induces an excess ACTH and cortisol response in CD patients and has rarely been used in pediatric patients, except in those with extremely difficult venous access [6]. Recently published articles investigated the reliability of CRH stimulation tests and HDDST and both concluded that the CRH test has greater specificity than HDDST [7, 8]. Elenius et al. suggested optimal response criteria as a ≥ 40% increase of ACTH and/or cortisol (cortisol as the most specific measure of CD) during the CRH test and a ≥ 69% suppression of serum cortisol during HDDST [7]. Using these criteria, the CD would be excluded in our patient. To demonstrate that the proposed thresholds for the test interpretation widely differ, Detomas et al. proposed a ≥ 12% cortisol increase and ≥ 31% ACTH increase during the CRH test to confirm CD [8].

The fact that up to 50% of PitNET may not be detected on MRI [1] and that more than 20% of patients with EAS are reported to have pituitary incidentalomas [9] makes MRI somewhat unreliable in differentiating CD and EAS. However, finally, well-established and generally reliable BIPSS in our patient supported the diagnosis of EAS. Thus, BIPSS is considered a gold standard to differentiate between CD and EAS; however, it can still provide false negative results in cyclic CS if performed in the trough phase [10] or in vascular anomalies or false positive results as in a recent case of orbital EAS [11].

In children, the presence of thymus tissue may be misinterpreted as normal. Among other reports of thymic NET [12], Hanson et al. reported a case of a prepubertal boy in whom a small thymic NET was initially treated as normal thymus tissue on CT [13]. In our case, initially, the lesion was not detected on the 18F-FDG and 68Ga-DOTATOC PET scans. A small thymic NET was visible only after a detailed and careful re-reading of both PET scans. Although somatostatin receptor (SSR) PET imaging may be helpful in identifying ectopic CRH- or ACTH-producing tumors, there are still some limitations [13]. For example, in the study by Wannachalee et al., 68Ga-DOTATATE identified suspected primary lesions causing ECS in 65% of patients with previously occult tumors and was therefore concluded as a sensitive method for primary as well as metastatic tumors [14]. In our patient, the final correct diagnosis was based on the results of both PET scans. This is in full support of the article published by Liu et al. who concluded that 18F-FDG and SSR PET scans are complementary in determining the proper localization of ectopic ACTH production [15]. Additionally, it is worth noting that not all NETs stain positively for ACTH which may present a burden in its identification.

To control hypercortisolemia, both ketoconazole and metyrapone were considered in our patient. Due to the side effects of metyrapone on blood pressure, ketoconazole was started as a preferred option in our pediatric patient. A retrospective multicenter study concluded that ketoconazole treatment is effective with acceptable side effects, with no fatal hepatitis and adrenal insufficiency in 5.4% of patients [3]. During ketoconazole treatment, our patient developed adrenal insufficiency; however, it is impossible to conclude whether this was solely due to ketoconazole treatment or whether an ongoing COVID-19 infection contributed to the adrenal insufficiency or whether this was caused by a phase of lower or no ACTH secretion from the tumor often seen in patients with cyclic ACTH secretion. The patient’s cyclic ACTH secretion is highly probable since her morning cortisol was slightly lower and ACTH was normal, even after being off ketoconazole treatment for 3 weeks.

When retrospectively and carefully reviewing all approaches to the diagnostic and management care of our pediatric patient, it would be essential to proceed to BIPSS before any pituitary surgery, especially when obtaining discrepant results from stimulation tests, as well as detecting a discrete pituitary lesion (≤ 6 mm) as recommended by the current guidelines [16]. This was our first experience using ketoconazole in a young child, and although this treatment was associated with very good outcomes in treating hypercortisolemia, close monitoring, and family education on signs and symptoms of adrenal insufficiency are essential to recognizing adrenal insufficiency promptly in any patient with EAS, especially those presenting also with some other comorbidities or stress, here COVID-19 infection.

In conclusion, the pediatric patient here presenting with EAS caused by thymic NET needs very careful assessment including whether cyclic CS is present, the outline of a good management plan to use all tests appropriately and in the correct sequence, monitoring carefully for any signs or symptoms of adrenal insufficiency, and apply appropriate imaging studies, with experienced radiologists providing accurate readings. Furthermore, ketoconazole treatment was found to be effective in reducing the symptoms and signs of CS in this pediatric patient. Finally, due to the rarity of this disease and the challenging work-up, we suggest that a multidisciplinary team of experienced physicians in CS management is highly recommended.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACTH:
Adrenocorticotrophic hormone
BIPSS:
Bilateral inferior petrosal sinus sampling
CD:
Cushing disease
CRH:
Corticotropin-releasing hormone
CS:
Cushing syndrome
CT:
Computed tomography
DST:
Dexamethasone suppression test
EAS:
Ectopic adrenocorticotropic hormone syndrome
18F-FDG PET:
Fluorine-18 fluorodeoxyglucose positron emission tomography
HDDST:
High-dose dexamethasone suppression test
IV:
Intravenous
LDDST:
Low-dose dexamethasone suppression test
NET:
Neuroendocrine tumor
PitNET:
Pituitary neuroendocrine tumor
UFC:
Urinary free cortisol

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Acknowledgements

The authors thank all the colleagues from the Thomayer University Hospital and Military University Hospital who were involved in the inpatient care of this patient.

Funding

This work was supported by the Charles University research program Cooperatio Pediatrics, Charles University, Third Faculty of Medicine, Prague.

Author information

Authors and Affiliations

  1. Department of Children and Adolescents, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 50, Prague, 100 34, Czech Republic

    Irena Aldhoon-Hainerová

  2. Department of Pediatrics, Thomayer University Hospital, Prague, Czech Republic

    Irena Aldhoon-Hainerová

  3. Department of Medicine, Military University Hospital, Prague, Czech Republic

    Mikuláš Kosák

  4. Third Department of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

    Michal Kršek

  5. Institute of Nuclear Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

    David Zogala

  6. Developmental Endocrinology, Metabolism, Genetics and Endocrine Oncology Affinity Group, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA

    Karel Pacak

Contributions

All authors made individual contributions to the authorship. IAH, MK, MK, and DZ were involved in the diagnosis and management of this patient. DZ was responsible for the patient´s imaging studies. IAH wrote the first draft of the manuscript. KP revised the manuscript critically. All authors reviewed and approved the final draft.

Corresponding author

Correspondence to Irena Aldhoon-Hainerová.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Signed informed consent was obtained from the patient and the patient´s parents for the publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.

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https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-024-01756-5

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Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing’s Syndrome

Posted on November 9, 2024 by MaryO

Julie Lavoillotte, Kamel Mohammedi, Sylvie Salenave, Raluca Maria Furnica, Dominique Maiter, Philippe Chanson, Jacques Young, Antoine Tabarin
The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 11, November 2024, Pages 2882–2891
https://doi.org/10.1210/clinem/dgae258

Abstract

Context

Current guidelines for distinguishing Cushing’s disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients.

Objective

To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters.

Design

Retrospective study.

Setting

University hospitals.

Patients

Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation.

Results

Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92–.99] in the primary study and .99 [95% CI, .98–1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97–1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3–10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value.

Conclusion

UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.

Read the article here: https://academic.oup.com/jcem/article/109/11/2882/7645065

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Ectopic Cushing Syndrome in Metastatic Castration‑Resistant Prostate Cancer

Posted on August 14, 2024 by MaryO

Abstract

Cushing’s syndrome (CS), as a result of ectopic adrenocorticotropic hormone (ACTH) production, constitutes a common paraneoplastic manifestation of various malignancies, with the most common being small cell lung carcinoma. In the literature, fewer than fifty cases associating ectopic CS with prostate cancer have been documented. In the present study, the case of a 76‑year old man suffering from castration‑resistant prostate adenocarcinoma that had been treated with enzalutamide and luteinizing hormone‑releasing hormone (LHRH) analogue for the last four years is presented. The patient presented to the emergency department with lower extremity muscle weakness, bradypsychia and hypokalemia. Following a thorough diagnostic evaluation, hypercortisolemia was identified. No suppression after low‑ and high‑dose dexamethasone challenge, increased cortisol 24 h excretion and normal pituitary magnetic resonance imaging led to the diagnosis of ectopic CS. Immediate targeted therapy was initiated with adrenal steroidogenesis inhibitors, including metyrapone and ketoconazole along with chemotherapy with docetaxel and prednisolone. There was a remarkable decrease in cortisol levels within days and hospitalization was no longer required. The patient managed to complete three cycles of chemotherapy; unfortunately, he succumbed within three months of the diagnosis of ectopic CS. In the present study, all existing cases of paraneoplastic CS related to prostate cancer are reviewed. The aim of the current study was to highlight the need of early diagnosis and treatment of this entity as it may present with atypical clinical findings and potentially evolve to a life‑threatening condition.

Introduction

Prostate cancer is the second most common cancer in males accounting for more than 900,000 cases per year (1). Adenocarcinoma is by far the most common subtype and affects more than 95% of the patients (2). Androgen deprivation therapy (ADT) remains the cornerstone of treatment for metastatic prostatic adenocarcinoma. Despite the initial response to androgen blockade, castration resistance often occurs via multiple mechanisms through androgen receptor (AR) pathway or others. Neuroendocrine dedifferentiation is one of the AR-independent castration resistance mechanisms that lead to an aggressive phenotype (3,4). While neuroendocrine differentiation in prostate cancer (NEPC) is a rare phenomenon in primary prostate cancer (<2%), it is detected in up to 10–17% of metastatic castrate-resistant prostate cancer (3). In addition, NEPC is often observed among males who have been previously treated with ADT or radiotherapy for prostate cancer (4,5). These types of tumors express typical neuroendocrine markers such chromogranin, synaptophysin (SYP) and specific neuronal enolase (NSE) but lack the expression of AR and AR-mediated genes (3,5). These tumors may originate de novo from a small population of neuroendocrine cells present in the prostate but usually occur from a population of luminal-derived castration-resistant cells through a neuroendocrine differentiation (NED) or trans-differentiation process. This phenotypic change can lead to a more aggressive clinical presentation with atypical manifestations and fewer effective treatment options. Bioactive substances produced by these cells can lead to paraneoplastic syndromes, including ectopic adrenocorticotropic hormone (ACTH) secretion. In the present study, a case of paraneoplastic Cushing syndrome (CS) in a patient with metastatic prostate cancer is presented. A review of the literature on this rare clinical entity is also presented to improve characterization of the clinical features and prognosis.

Case report

A 76-year old patient with a four-year history of metastatic prostate adenocarcinoma presented to the emergency department due to rapid-onset lower extremity weakness. The patient was first diagnosed with de novo metastatic prostate cancer in 2019 and was under ADT with enzalutamide and luteinizing hormone-releasing hormone analogue for the last four years. Biopsy of the prostate was performed in 2019 and revealed an adenocarcinoma Gleason 8 (5+3) of the prostate. Prostate-specific antigen (PSA) at initial diagnosis was 12.5 ng/ml and declined progressively to 0.007 ng/ml in 2022 after the initiation of enzalutamide. The patient now presented with lumbar pain and thus a magnetic resonance imaging (MRI) of the lumbar spine was performed which revealed the presence of an intraspinal metastasis in front of the fourth lumbar vertebra causing spinal cord compression. CT scans of the chest and abdomen showed an additional soft tissue metastasis on the left iliac bone and regional lymph node metastases. The patient started palliative radiotherapy at the metastatic foci of the O4 lumbar vertebrae and left iliac bone and was about to initiate chemotherapy with docetaxel. Of note, baseline PSA at disease progression was 0.48 ng/ml before the administration of chemotherapy.

The patient presented at the Emergency Department on the 13th of June 2023 with lower extremity muscle weakness and hypokalemia (2 mEq/l). He was hemodynamically stable and on inspection he appeared pale. Neurologically, he was oriented but exhibited emotional lability with bradypsychia. There were no focal neurological deficits in the lower extremities. Laboratory findings showed marked hypokalemia with serum potassium level of 2 mEq/l (3,5-5,1 mEq/l), metabolic alkalosis (HCO3: 48,5 mEq/l) and an elevated lactate dehydrogenase level of 461 U/l (135–225 U/l). Electrocardiogram revealed a prolonged QT interval with a corrected QT interval of 473 ms. The patient received intravenous and oral potassium supplements to prevent life-threatening arrhythmias and further investigation of hypokalemic alkalosis was initiated. The laboratory findings of the initial assessment are demonstrated in Table I.

No episodes of diarrhea or vomiting were reported from recent medical history, thus potassium loss from the gastrointestinal tract was excluded. Additionally, urine electrolytes were within normal limits, hence renal potassium loss was also excluded. Therefore, endocrinological causes of hypokalemia were investigated. An adrenal protocol CT scan was performed which revealed no pathologic findings. Based on the aforementioned findings, evaluation of renin, aldosterone, ACTH and cortisol levels was requested. Τhe aforementioned tests revealed normal renin and aldosterone levels but elevated plasma cortisol levels >1,380 nmol/l (138–690 nmol/l) along with elevated plasma ACTH levels 194 pg/ml (<46 pg/ml). Measurement of 24 h urinary free cortisol revealed a value of 20,600.00 µg/gCr (1.00–119.00 µg/gCr). There was no suppression after both low-dose and high-dose dexamethasone challenge. Pituitary MRI was performed but revealed no pathologic findings (Fig. 1). Consequently, the patient was diagnosed with CS and ectopic ACTH production was considered the most likely diagnosis associated with paraneoplastic syndrome in the context of metastatic prostate adenocarcinoma.

Clinical deterioration was acute and thus both symptomatic treatment and chemotherapy were initiated. Symptomatic treatment included oral potassium supplements, potassium-sparing diuretics, along with mineralocorticoid blockade (spironolactone). Treatment with ketoconazole 200 mg and metyrapone 500 mg three times per day, which block the steroid biosynthetic pathway, was initiated. Additionally, anticoagulant therapy was administered due to increased risk of thromboembolism. The patient remained under close monitoring throughout the course of his treatment and did not experience any treatment-related adverse events, including hepatotoxicity, which is most commonly reported. On the 10th day of treatment with ketoconazole and metyrapone, lab tests revealed a decrease in serum cortisol levels (425 nmol/l) and ACTH levels (129 pg/ml) along with the stabilization of potassium levels (Fig. 2A and B). Following the clinical and laboratory stabilization of the patient, chemotherapy with docetaxel 75 mg/m2 and prednisolone 5 mg bid was initiated. The patient was discharged from hospital after one month of hospitalization and continued chemotherapy. PSA declined from 0.48 to 0.22 ng/ml after three cycles of docetaxel administration. However, the patient died three months after initial presentation despite his initial response to treatment.

Discussion

Ectopic CS constitutes a rare paraneoplastic entity in prostate cancer. Ectopic CS as a paraneoplastic syndrome accounts for only 10–15% of CS cases and is mostly related to small cell lung cancer, pancreatic, thymus or thyroid carcinoma (6). This case highlights the urgency of diagnosing this entity and the importance of initiating treatment promptly. A case of ectopic ACTH production in a patient with castration-resistant metastatic prostate cancer who had previously received enzalutamide plus ADT is presented in the current study. Despite prompt diagnosis of ectopic Cushing disease and immediate initiation of treatment with ketoconazole and metyrapone, the patient deteriorated and eventually succumbed at three months after initial presentation with CS.

The existing literature for cases of CS related to prostate cancer was reviewed. The search strategy consisted of the following keywords: ‘cushing syndrome’ AND ‘prostate cancer’ that was applied to PUBMED bibliographical database (https://pubmed.ncbi.nlm.nih.gov/). Overall, a total of 102 papers were retrieved from the search algorithm. After the removal of two review articles (7,8) as well as two non-English papers (9,10), a total of 26 articles were considered eligible for this review (11–36). An additional search of the literature cited in the aforementioned papers revealed 12 more eligible papers (37–48). Finally, a google research was performed that revealed three additional papers (49–52). The search algorithm is illustrated in Fig. 3 and all the cases identified are summarized in Table II. Papers reporting neuroendocrine differentiation of the prostate with positive ACTH staining without clinical manifestations of ACTH serum production were excluded (53–58).

The first case reports of ectopic ACTH production in patients with prostatic carcinoma date back to the 1960s written by Webster et al (38) and Jarett et al (56). However, either tissue staining for ACTH was not available (38) or the primary tumor displayed no staining with the fluorescent anti-ACTH (56). The first well-documented case report of a patient with prostatic adenocarcinoma producing ACTH was presented by Newmark et al (37). Since then, several other cases of ectopic CS related to prostate cancer have been reported and are summarized in Table II. CS is a result of the ectopic production of ACTH in all of the cases except for two cases where corticotropin-releasing hormone (CRH) produced by the prostatic tumor is the driving cause (13,14). Indeed, CRH production from prostate cancer implicates 14% of the cases and is considered as an extremely rare source of ectopic ACTH (1–3%) (59). Histologically, CS emerged from small cell carcinoma of the prostate in 18 cases (11,13–15,20–22,24,25,27,29–31,33,34,47,50,51), neuroendocrine carcinoma of the prostate in five cases (17,21,26,28,32), prostate adenocarcinoma usually poorly differentiated/undifferentiated in 16 cases (16,18,19,23,35–39,41,42,44–46,49,52), anaplastic carcinoma in two cases (12,19) and carcinoid tumor of the prostate in another two cases (40,43). In the vast majority of the cases disease was metastatic with distant visceral metastases except for 11 cases (11,18,19,22,30,33,40,41,47,49,51) where disease was either locally advanced or metastatic only to lymph nodes.

Interestingly, the typical clinical manifestations of CS with centripetal obesity, moon facies, purple striae, buffalo hump and skin hyperpigmentation are rarely present (12,17,23,31,36,47). In most cases, muscle weakness, mental changes mild hypertension and edema are the presenting symptoms along with hypokalemic alkalosis and elevated glucose levels from laboratory tests (11,13–16,18–22,24–30,32–35,37–41,43–46,49–52). In the present case, the main clinical feature was limb muscle weakness combined with severe hypokalemic alkalosis. This comes in agreement with the existing literature which identifies hypokalemic alkalosis as often the only initial manifestation of the syndrome. This clinical picture reflects the rapid onset and aggressiveness of the syndrome. Most patients die early because of the underlying malignancy before the development of typical Cushing’s symptoms. Indeed, typical Cushing’s signs and symptoms develop under the condition of long-term hypercortisolism, so ectopic CS tends to present with less dramatic features, but higher blood pressure and more profound electrolyte abnormalities. Laboratory findings typically include hypokalemic alkalosis, elevated plasma glucose along with elevated plasma cortisol and ACTH levels and increased glucocorticoid excretion in urine as in the present case.

Initiation of supportive medication with oral or intravenous potassium supplements may be required. Treatment of CS is based on adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, mitotane or mifepristone (14,16–23,25–28,31–35,37,43–45,47,49–52) in over half of the cases (28/43; 65%) and more rarely etomidate (17,33) (2/43; 5%), as well as the newest therapeutic agent osilodrostat. Hypercortisolism may be controlled by blocking one or more adrenal enzymes, such as mitotane and metyrapone that inhibit 11β-hydroxylase or ketoconazole that inhibits both 17α-hydroxylase and 17,20-lyase. Interestingly, the somatostatin receptor ligand pasireotide is approved for patients with CS who have persistent or recurrent hypercortisolism and the dopamine agonist cabergoline facilitates initial normalization of urinary free cortisol levels and also improves the signs and symptoms of hypercortisolism. The cornerstone of treatment however remains the surgical removal of the tumor when is feasible. However, most of the ectopic ACTH-producing tumors are not resectable while patients may not be clinically fit enough for surgery. In these cases, supportive medication with antiglucocorticoid drugs is the preferred treatment option along with chemotherapy for the primary tumor. Chemotherapy was administered in one third of the cases (14/43) (13,17,19,21,22,24–27,31,35,47,52) and was mainly based on platinum-etoposide combinations. Whatever the treatment, prognosis is abysmal and median survival is as reported (Table II).

Neuroendocrine cells that lack androgen receptors are normally part of the normal prostate tissue and play a regulatory role in proliferation and secretion of the prostate epithelium (6,60). Neuroendocrine cells constitute only <1% of total epithelial cells found in prostate tissue and serve a paracrine or local regulatory role by secreting serotonin, calcitonin and other peptides (60). The inappropriate production of ACTH is attributed to these neuroendocrine cells that are part of the amine precursor uptake and decarboxylation (APUD) regulatory system (60). Neuroendocrine APUD cells are dispersed in numerous organs and systems in small concentrations such as gastrointestinal tract, lung and prostate and serve as one of the most important mechanisms of homeostasis. These cells have common biochemical and cytological properties as well as the ability to secrete polypeptides that include ACTH, neuron-specific enolase (NSE) and chromogranin A (CGA) (60). In vitro experiments have revealed that during androgen deprivation treatment (ADT), prostate adenocarcinoma cells have the capacity to transdifferentiate to a neuroendocrine (NE) phenotype, a process called neuroendocrine trans-differentiation. De novo prostate neuroendocrine carcinoma (small cell or large cell) is a rare entity (<2%), however treatment-emergent neuroendocrine neoplasms account for 10–17% of patients with metastatic CRPC (3). Indeed, a substantial population of pre-treated end-stage prostate cancer patients show salient features of de novo neuroendocrine small cell carcinomas, mostly with an aggressive behavior and often with visceral metastases. Radiotherapy and androgen deprivation therapy activate the process of neuroendocrine dedifferentiation through the following mechanisms: Either they induce malignant transformation of neuroendocrine cells within adenocarcinoma cells or they facilitate the growth of pre-existing neuroendocrine cells. In this manner, cancer cells lack androgen receptors and transform into castration-resistant prostate cancer cells resulting in disease progression. Although most patients are not routinely biopsied in end-stage disease, it has been estimated that at least 25% of the patients with advanced prostate cancer will develop neuroendocrine prostate cancer under androgen deprivation pressure (4). Neuroendocrine prostate carcinoma differs from the conventional adenocarcinoma of the prostate histologically by expressing neuroendocrine markers such as chromogranin A, SYP, CD56, and NSE instead of prostate adenocarcinoma markers like AR, P501S, PSMA, PSAP and PSA (61). Of note, the introduction of next generation antiandrogen agents like enzalutamide or abiraterone resulted in an increase of neuroendocrine prostate carcinomas from 6.3 to 13.3% after 2012 (3). Paraneoplastic syndromes associated with prostate cancer are rare. However, when they occur, they constitute the initial clinical manifestation of prostate cancer in up to 70% of cases and a sign of progression to castration-resistance in 20% of cases (62). Paraneoplastic syndromes often related to prostate cancer include endocrine syndromes (inappropriate antidiuretic hormone secretion, CS, hypercalcemia) as well as hematological disorders and neurological syndromes (62).

Pure carcinoids of the prostate are rare, while mixed carcinomas of prostate adenocarcinoma and carcinoid are more frequent. Small cell prostate carcinoma accounts for ~0.5–2% of prostate carcinoma cases (63). It is thought that small cell carcinoma of the prostate has a common origin with prostate adenocarcinoma as ~40–50% of men with small cell carcinoma of the prostate have a prior or concurrent history of prostatic adenocarcinoma (63). Based on the aforementioned information, ectopic ACTH production mainly emerges from the neuroendocrine transformation of the preexisting prostate adenocarcinoma. This raises the question of performing re-biopsy to histologically confirm the diagnosis. However, the imminent need to initiate treatment early may postpone the performance of a confirmatory re-biopsy. As known, the state of extreme hypercortisolism creates a fertile environment for infections. Therefore, the prompt initiation of targeted treatment with metyrapone or ketoconazole and potassium supplements to target hypercortisolism in combination with chemotherapy for the underlying malignancy may be deemed more urgent. This case was thoroughly discussed in multidisciplinary medical meetings focusing on the best therapeutic approach. In accordance with the present case, re-biopsy was not performed in most of the cases identified in the existing literature mainly due to the fast deterioration of the patient and the subsequent lack of time. Indeed, most patients die from sepsis secondary to uncontrolled CS. This is the reason that suppression of the hypercortisolism is urgent and should not be delayed to identify the source of CS.

In conclusion, the ectopic CS can be a clinical manifestation of prostate cancer. It requires timely diagnosis and aggressive treatment to avoid life-threatening complications of hypercortisolemia. The present case highlighted the necessity of multiple laboratory and imaging examinations required for the definitive diagnosis of CS, with the ultimate goal of initiating targeted therapy promptly.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be found in the PUBMED database at the following URL: https://pubmed.ncbi.nlm.nih.gov.

Authors’ contributions

FZ, MAD and SAP conceptualized the study. AA, KG and KS conducted the investigation. FZ, MAD and SAP supervised the study. AA, KG, SA and KS were involved in drafting the original manuscript and revised it critically for important intellectual content. SA also made a substantial contribution to the analysis and interpretation of the data, gave final approval for the manuscript to be published and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript. KG and AA confirm the authenticity of all the raw data.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

The patient provided written informed consent for this case study to be published.

Competing interests

MAD has received honoraria from participation in advisory boards from Amgen, Bristol-Myers-Squibb, Celgene, Janssen, Takeda. FZ has received honoraria for lectures and has served in an advisory role for Astra-Zeneca, Daiichi, Eli-Lilly, Merck, Novartis, Pfizer, and Roche. The remaining authors declare no competing interests.

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A Challenging Case of Severe Cushing’s Syndrome in the Course of Metastatic Thymic Neuroendocrine Carcinoma with a Synchronous Adrenal Tumor

Posted on August 8, 2024 by MaryO

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%–10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

1 Introduction

Endogenous Cushing’s syndrome (CS) is a rare endocrine condition caused by excess cortisol production with an annual incidence of 0.2–5 cases per million people (1). Adrenocorticotropin (ACTH) hypersecretion of nonpituitary tumors leading to ectopic ACTH syndrome (EAS) accounts for 9%–18% of ACTH-dependent CS cases (1, 2) and represents one of the most common paraneoplastic syndromes (3, 4). Neuroendocrine tumors (NETs) of various locations, degrees of histological differentiation, and aggressiveness potential can lead to EAS; however, most frequently, they derive from the foregut, with the well-differentiated bronchial NET being the most common one in recent series (5, 6). NETs of the thymus (NETTs) represent up to 5% of all thymic tumors, with an incidence of 0.02 per 100,000 people per year in the Caucasian population (7, 8). Up to 50% of the hormonally active NETTs present with ACTH hypersecretion (8) that account for 5%–10% of EAS cases (5, 9). They usually behave aggressively with regional invasion and early distant metastases and lead to the rapid development of severe hypercortisolism (SH), which worsens the initial poor prognosis (8–11).

Herein, we present a unique case of a patient with EAS caused by a primary metastatic, ACTH-secreting thymic large-cell neuroendocrine carcinoma (LCNEC) with an atypical carcinoid (AC) component with rapid progression, which initially failed to be visualized in imaging studies. Moreover, the diagnostic process was even more difficult because of the co-presence of an adrenal lesion suspected of malignancy on imaging studies and to be the primary origin of the disease.

2 Case report

In April 2019, a 31-year-old previously healthy woman presented to the Emergency Department with a 3-week history of progressing fatigue, muscle weakness, exercise intolerance, headaches, progressive hypertension, generalized swelling, polyuria, polydipsia, and nycturia. Due to the reported symptoms, the patient had previously consulted a family doctor, who initiated oral potassium supplementation because of hypokalemia (2.8 mmol/L) found in basic laboratory tests. On physical examination, the patient presented with significant peripheral pitting edema, high blood pressure (170/100 mmHg), tachycardia (170 beats/minute), and acne lesions on the face, back, and chest. The initial laboratory tests at the Emergency Department showed the following: leukocytosis (13.95 × 109/L) with neutrophilia (12.98 × 109/L) and lymphopenia (0.27 × 109/L), hypochloremic metabolic alkalosis (pH 7.52; HCO3−, 38.3 mmol/L; and Cl−, 91 mmol/L), hyperglycemia (478 mg/dL), and profound hypokalemia (2.2 mmol/L). Initial laboratory findings are summarized in Table 1A.

Table 1a

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Table 1A Summary of initial laboratory test performed at Emergency Department.

Within the Emergency Department, the patient was considered as a patient with newly diagnosed diabetes and was referred to the Endocrinology Department, where she was started on insulin therapy along with aggressive hypokalemia repletion, antihypertensive treatment, and preventive heparin anticoagulation. Given the overall clinical presentation and resistance to initiated treatment, aggressive CS was quickly suspected. During the first days of hospitalization, the patient also developed agitation with paranoid symptoms; thus, the psychiatrist was consulted, and the patient was additionally started on antipsychotic treatment.

The hormonal evaluation revealed SH with high concentrations of morning (78.2 μg/dL; reference range, 3.7–19.4) and midnight (69.1 μg/dL; reference range, < 5.4) serum cortisol, 24 h urinary free cortisol (UFC) excretion exceeding 65 times the upper reference limit (11,587.5 μg/24 h; reference range, 4.6–176.0), and hyperandrogenemia (testosterone, 6.3 ng/mL; reference range, 0.06–0.8; DHEA-S, 853.2 μg/dL; reference range, 95.8–511.7). ACTH level was markedly elevated (963.7 pg/mL; reference range, 6.0–48.0), confirming ACTH-dependent CS. No dynamic hormonal testing was performed, considering the severe state of the patient. The hormonal findings are summarized in Table 1B.

Table 1b

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Table 1B Summary of initial hormonal assessment in presented patient.

To control SH, continuous etomidate infusion was initiated with significant improvement in the patient’s general condition, edema reduction and normalization of blood pressure, glycemia, and potassium level with a decrease in the need for antihypertensive and insulin treatment, mineralocorticoid receptor blockade, and potassium supplementation. Pituitary magnetic resonance imaging (MRI) revealed no lesion. ACTH-dependent SH with negative pituitary imaging and short duration with rapid progression of symptoms were highly suggestive of EAS. Computed tomography (CT) of the chest, abdomen, and pelvis was performed and revealed a left, inhomogeneous, solid adrenal mass measuring 80 mm ×56 mm ×39 mm of 25 Hounsfield units adjacent to/infiltrating the left dome of the diaphragm, hyperplasia of the right adrenal gland, and numerous sclerotic bone lesions concerning for metastases (Figure 1).

Figure 1

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Figure 1 Frontal (A) and axial (B) CT scans of the abdomen presenting a large lesion of the left adrenal gland. 18F-FDG-PET-CT presenting high metabolic activity of the left adrenal gland lesion (C1, C2) and metastatic bone lesions in the spine and sternum (D).

Plasma and urine metanephrines, renin, and aldosterone levels were within the reference range (Table 1B). However, an excessively elevated concentration of chromogranin A (CgA) was observed (13,835.0 ng/mL; reference range, < 100), which firmly suggested the presence of a NET. The patient underwent whole-body SPECT-CT somatostatin receptor scintigraphy (SRS) with 99mTc-octreotate, which showed no evidence of somatostatin receptor overexpression. Subsequently, whole-body 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was performed and revealed that the left adrenal gland lesion previously found on CT scan is partially metabolically active [maximum standardized uptake value (SUVmax), 3.2] and suspicious of malignancy; the right adrenal gland presented diffused 18F-FDG uptake (SUVmax, 2.6) likely resulting from excessive ACTH overstimulation. 18FDG-PET-CT also showed multifocal metabolically active sclerotic bone lesions in the spine, ribs, clavicles, scapules, sternum, pelvis, femurs, and humerus. A SUVmax 2.1 area (not correlated with CT imaging) was also found in the anterior mediastinum, which has been considered primarily as a residual thymus with physiological FDG uptake (Figure 1).

The clinical presentation was highly suggestive of generalized malignancy with ectopic ACTH secretion with the potential origin in the left adrenal gland. The patient was discussed at a multidisciplinary team meeting and was decided to undergo left-sided open adrenalectomy. After the surgery, the symptoms of hypercortisolemia resolved, the etomidate infusion could have been stopped, and the patient did not require further use of antihypertensive and insulin treatment, mineralocorticoid receptor blockade, and potassium supplementation. Furthermore, postoperatively, a significant decline in cortisol levels was noted (4.08 μg/dL), and the patient was transitioned to oral hydrocortisone. ACTH level also dropped (312.0 pg/mL 2 h after morning dose of oral hydrocortisone); however, it still remained significantly elevated. While waiting for the histopathological result, the patient underwent additional colonoscopy, gastroscopy, and bronchoscopy, but no other potential cancer origin was found. We consulted with the oncologist, and active surveillance was recommended until the histopathological examination results were obtained. The patient was discharged after 5 weeks of hospitalization, awaiting the result of the histopathological examination, in good general condition, requiring only hydrocortisone substitution.

The histopathological examination revealed an adrenal adenoma with the domination of adrenal infarction and necrosis. Immunohistochemistry (IHC) showed the following: CgA (+), EMA (−), synaptophysin (−), S100 (−), CKAE1/AE3 (+), RCC (−), melan-A (−), Ki-67 positive in single adrenal cells. Although its diagnosis was unlikely, according to the histopathology and IHC, it was not possible to clearly exclude the adrenocortical cancer (ACC). However, given ACTH-dependent hypercortisolemia and significantly elevated CgA concentration, an undetected neuroendocrine tumor was considered first.

A follow-up 18F-FDG-PET-CT performed after 8 weeks revealed a metabolically active mass (SUVmax, 9.3) in the superior anterior mediastinum in the thymus location (Figure 2A). CT (Figure 2B) and the subsequently performed MRI (Figure 2C) of the chest confirmed mediastinal mass measuring 42 mm × 33 mm, adjacent to the trachea and superior vena cava, encircling the ascending aorta and aortic arch, most likely corresponding to the invasive thymic malignancy.

Figure 2

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Figure 2 Eight-week follow-up 18F-FDG-PET-CT presenting metabolically active lesion in the superior anterior mediastinum in the thymus location (A1, A2). Axial CT (B) and MRI (C) scans of the chest presenting mediastinal mass corresponding to the invasive thymic malignancy.

The patient was qualified for a thoracic surgery; however, due to the local invasion, it was only possible to perform a partial thymectomy (August 2019). After the procedure, the ACTH concentration dropped but not significantly (537.3 pg/mL before and 446.0 pg/mL after the surgery). A histopathology report revealed thymic LCNEC with AC component extensively infiltrating the surgical margins. On IHC, the tumor stained positive for CgA, synaptophysin, and CD56, and weakly for ACTH; the Ki-67 index was 40%, p53 expression was 70% (Figure 3). The final diagnosis was TNM stage IVB (pT2NxM1b), Masaoka–Koga stage III ACTH-secreting combined thymic LCNC and AC.

Figure 3

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Figure 3 Large-cell neuroendocrine carcinoma of the thymus with atypical carcinoid morphology, pathological diagnosis. (A) Microscopic image of the primary tumor, HE staining. (B) Weak positive IHC staining for ACTH. (C) Microscopic image of the brain metastasis, HE staining. (D) Weak positive IHC staining for ACTH of the brain metastasis. (E) Electron microscopic image of cancer cells; the material was taken from a paraffin block, which resulted in a poorly preserved ultrastructure. Visible neuroendocrine granules concentrated around the cell nucleus (×17,500). (F) Ultrastructural image of the neuroendocrine granules with a diameter of (×24,500).

As part of the cancer multidisciplinary team meeting, the patient was qualified for postoperative radiotherapy (RTH) for the thymus bed and residual mass of the mediastinal tumor. Between October and December 2019, the patient received 64 Gy/t in 2 Gy/t fraction doses. Unfortunately, the ACTH concentration increased during the RTH to the maximum observed value of 1,021.2 pg/mL, which suggested further progression of the disease. Follow-up 18F-FDG-PET-CT (January 2020) showed a thymic mass measuring 31 mm × 20 mm, less metabolically active (SUVmax, 4.3) than initially. It also revealed a new 18F-FDG-avid lesion in the pancreas tail in the left temporal lobe (SUVmax, 12.7). The brain MRI confirmed the presence of metastasis measuring 30 × 24 × 18 mm. The patient was qualified for postoperative chemotherapy (CTH) according to the ADOC regimen (cisplatin, doxorubicin, vincristine, and cyclophosphamide) for aggressive thymic tumors (January 2020–May 2020). CTH resulted in disease partial response, and ACTH concentration dropped to 192.0 pg/mL. In June 2020, the patient underwent a craniotomy with left non-radical temporal tumor resection and received additional RTH. The disease was stable for almost 10 months; however, the follow-up 18F-FDG-PET-CT on May 2021 showed new active lesions in the right lung, pancreas, left iliopsoas muscle, and left breast. ACTH level at that time increased to 655.5 pg/mL. The patient was introduced to the PE regimen CTH (cisplatin and etoposide, June 2021–September 2021) with a short-term partial response. Because of the further disease progression, the patient was started on palliative CTH. More than 3.5 years after the first hospitalization, in November 2022, the patient passed away.

3 Discussion

In this paper, we present a unique case of a patient with ACTH-secreting combined thymic LCNEC with AC component, primary manifested as severe CS. NETTs constitute approximately 2%–5% of thymic tumors (7–9), representing approximately 2% of all mediastinal tumors (8). NETTS are typically diagnosed with a mean age of 55, with a clear male predominance (male-to-female ratio, 3:1) (7). EAS with ACTH secretion occurs in up to 50% of hormonally active NETTS (8). NETTs associated with EAS appear in younger populations below age of 40 compared to overall NETTs and are also more prevalent in male individuals (albeit in a lower proportion when compared to non-EAS NETTs) (9). EAS-related NETTs have a worse outcome than biochemically inactive thymic tumors, since they usually have an aggressive course, with early regional invasion, distant metastasis, and high mortality (8–11). Patients with EAS typically present with rapid-onset, severe CS, including resistant hypertension, hyperglycemia, profound and refractory hypokalemia with metabolic alkalosis, generalized edema, and proximal muscle weakness (4–6). SH, which occurs in approximately 60% of patients with hormonally active NETTs secreting ACTH (and approximately 80% in the case of ACTH-secreting thymic carcinomas), significantly worsens the initial poor prognosis (9). In the systematic review by Guerrero Pérez et al., mortality in patients with advanced disease was approximately 55%, and the median time between diagnosis and death was 38 months (9). NETTs are typically large tumors that could manifest with neoplastic mass effect (11, 12); however, only up to 10% of patients with ACTH-secreting NETTs present with local compressive symptoms (9).

In EAS, the progression of hypercortisolemia is typically accelerated, and patients with very rapid SH onset may not present with typical cushingoid features. During the initial assessment at the Emergency Department, the patient was overlooked—the physician’s attention was captured by diabetes mellitus, but the clinical features have not been linked to CS. It highlights the need for a high CS clinical suspicion in case of SH. The presence of profound hypokalemia in combination with hyperglycemia and resistant hypertension with edema is a clue that should prompt diagnosis (4, 5).

In the Endocrinology Department, the patient was quickly suspected of aggressive CS. Serum cortisol, UFC, and ACTH were dramatically increased. The patient was started on etomidate infusion to control hypercortisolemia. Etomidate is considered the most potent and effective agent for rapidly inhibiting cortisol overproduction (13, 14). Indeed, the patient’s clinical condition notably improved after only a few days of etomidate therapy with edema reduction and normalization of blood pressure, glycemia, and kalemia.

In the presented patient, the severity of hypercortisolemia with negative pituitary MRI image and positive whole-body CT imaging were compatible with EAS. Whole-body CT and functional imaging highly suggested a generalized malignancy with a potential origin in the left adrenal gland. The possibility of metastatic pheochromocytoma was considered—the concentration of CgA was significantly elevated, but urine and plasma metanephrines were negative. The ACC was also taken into consideration. Nevertheless, only one case of ACC potentially related to EAS was reported (15).

However, it is puzzling how only one of the adrenal glands was ACTH overstimulated, and the function of the second one seemed to be inhibited. A significant decline in cortisol concentration after exclusive unilateral adrenalectomy indicated that the left adrenal gland tumor could indeed have been the primary origin of malignancy and CS itself. On the other hand, ACTH level remained significantly elevated, although it dropped more than twofold compared to baseline. It was considered that the persistently elevated (but markedly lower) ACTH concentration was associated with the presence of metastases or could (albeit partially) result from the pituitary response to a significant decrease in cortisol concentration. Of course, metastatic ectopic ACTH-secreting tumor of unknown origin was also considered at that time.

Surprisingly, the histopathology examination revealed an adrenal adenoma with the domination of necrosis due to the adrenal infarction. It cannot be ruled out that the patient had a previously undiagnosed adrenal adenoma, and even short-term but dramatic ACTH hyperstimulation led it to its significant growth and provoked an adrenal infarction, imitating a malignancy in the imagery evaluation. Differentiating benign and malignant adrenal lesions based on 18F-FDG-PET-CT has a high diagnostic accuracy (16–18); however, metabolically active adenomas may present with increased FDG uptake and mimic malignancy (19). In addition, adrenal hemorrhage and necrosis can present with increased activity on 18F-FDG-PET-CT (20). Thus, it seems that the increased 18F-FDG avidity of the left adrenal lesion with foci of intratumoral necrosis was directly related to dramatically elevated ACTH concentrations and adrenal overstimulation.

CT scan located the EAS-related NETTs in 97.8% of cases in the aforementioned systematic review by Guerrero Pérez et al. (9). In the presented patient, imagery diagnostic initially failed to visualize the thymic tumor. There are only few reports on non-diagnostic chest CT or MRI evaluation in patients with EAS NETTs (21–23); however, in the presented cases, NETTs were found on SRS, which is contrary to our report. The first 18F-FDG-PET-CT localized an area of 2.1 SUVmax in the anterior mediastinum, initially considered a residual thymus because of the physiological FDG uptake. It is also unique how the PET-CT scan, chest CT, and MRI revealed a highly 18F-FDG-avid, large, invasive mediastinal mass just a few weeks after the baseline assessment. Imagery and functional studies were additionally retrospectively assessed by independent radiologists and nuclear medics to exclude a possible oversight during the initial analysis. However, it was maintained that there was no clear evidence of a thymic neoplasm at baseline.

Thymic carcinomas present with high FDG uptake, typically with SUVmax > 7 (24), SUV max values <4 as being most consistent with benign thymic processes (25). On the other hand, there is a marked overlap in FDG uptake between physiological thymic FDG uptake and thymic neoplasia in the literature, indicating that 18F-FDG-PET-CT has a limited ability to assess the thymus and an equivocal role in the differentiation of a normal thymus from thymic neoplasia (26). Among all described cases of EAS-related NETTs in the literature in which 18F-FDG-PET-CT was indicated as one of the diagnostic step, the primary tumor was visualized in all of them (27–38). The primary NETT SUVmax was reported only in five of them ranging from 2.48 to 12.0 (27–31); in the remaining ones, 18F-FDG avidity was reported from mild to high. However, in all mentioned cases (besides one (31), where no information about radiological chest imaging was reported), the NETT was previously visualized on chest CT, and 18F-FDG-PET-CT was performed to assess the disease staging rather than to find EAS origin.

On IHC, the thymic tumor stained weekly positive for ACTH in contrast to dramatically elevated plasma ACTH concentration. There seems to be a negative correlation between ACTH immunoreactivity and the neuroendocrine tumor malignancy potential. Moreover, the diagnosis of EAS is not ruled out in the case of primary tumor negative ACTH IHC staining. Less differentiated neuroendocrine tumors are believed to secrete ACTH rapidly and might also lose the ability to store ACTH in the secretory granules, thus leaving for typical techniques insufficient ACTH amounts stored to be stained (39, 40). In addition, the tumor might secrete various biologically active ACTH precursors that are negative on IHC.

Complete NETT resection is the only curative option and the strongest factor for overall survival (7, 41, 42). In the case of a subtotal resected tumor, RTH and CTH are considered (42–44); however, there is no consensus and guidelines for the optimal postoperative strategy, mainly due to the rarity of the disease. Systematic therapies are also used as palliative treatment in case of unresectable, metastatic, and recurrent NETTs (42, 44). Besides the primary metastatic disease, the presented patient underwent a partial resection with macroscopic residual tumor (R2) and was then qualified for postoperative RTH and CTH. After the R2 resection, postoperative RTH may be combined sequentially or concurrently with CTH (45). RTH was not clearly effective, as the follow-up 18F-FDG-PET-CT showed new metastases, including an extensive metastasis to the left temporal lobe. Several CTH regimens have been used in patients with NETTs (42, 44, 45). CTH response rates in metastatic poorly differentiated NETTs are 30%–50%, with progression-free survival rates of 6–9 months (45). The presented patient was introduced to an ADOC regimen, which resulted in a partial response. However, the patient started second-line and later palliative CTH because of the further disease progression.

4 Conclusions

We present a unique and challenging case of malignant, primary metastatic NETT initially manifesting with severe EAS and not visible in initial imaging studies in a patient with coexisting adrenal tumor suspected of malignancy and primary disease origin. The presented case highlights that the diagnosis and management of EAS remain challenging; it requires a high clinical suspicion, rapid hypercortisolemia control with symptomatic treatment of cortisol-induced comorbidities, and simultaneously complex imaging studies to determine the primary source of the ACTH hypersecretion. The treatment of choice is resection of ACTH-secreting NET; however, it may not be possible in patients with initially occult or metastatic disease. Malignant NETTs with ectopic CS are extremely rare, and their management has to be individualized in every case, requiring a multidisciplinary approach. Regardless, the prognosis remains poor due to the aggressiveness of the disease.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies were conducted in accordance with the local legislation and institutional requirements. The patient gave an oral consent for publication while alive. Written informed consent for publication was obtained from the patient’s parents.

Author contributions

LD: Resources, Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. AW-L: Writing – review & editing, Supervision, Resources, Methodology, Data curation, Conceptualization. MM: Writing – review & editing, Resources, Data curation, Conceptualization. PW: Writing – review & editing, Supervision, Resources, Methodology, Data curation.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The publication fee was covered by the Medical University of Warsaw.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: adrenal tumor, cortisol, ectopic ACTH syndrome, etomidate, thymic neuroendocrine carcinoma

Citation: Dzialach L, Wojciechowska-Luzniak A, Maksymowicz M and Witek P (2024) Case report: A challenging case of severe Cushing’s syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor. Front. Endocrinol. 15:1399930. doi: 10.3389/fendo.2024.1399930

Received: 12 March 2024; Accepted: 24 May 2024;
Published: 14 June 2024.

Edited by:

Vincent Geenen, University of Liège, Belgium

Reviewed by:

Mara Carsote, Carol Davila University of Medicine and Pharmacy, Romania
Aleksandra Gilis-Januszewska, Jagiellonian University Medical College, Poland

Copyright © 2024 Dzialach, Wojciechowska-Luzniak, Maksymowicz and Witek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lukasz Dzialach, lukasz.dzialach@wum.edu.pl

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